bims-raghud Biomed News
on RagGTPases in human diseases
Issue of 2024–11–10
six papers selected by
Irene Sambri, TIGEM
  1. mTORC1 activity licenses its own release from the lysosomal surface.
  2. mTORC1 restricts TFE3 activity by auto-regulating its presence on lysosomes.
  3. The dual role of the TSC complex in cancer.
  4. HSP70 promotes amino acid-dependent mTORC1 signaling by mediating CHIP-induced NPRL2 ubiquitination and degradation.
  5. Activation of lysosomal Ca2+ channels mitigates mitochondrial damage and oxidative stress.
  6. Targeted therapeutic strategies for the kidney.
  1. Mol Cell. 2024 Oct 25. pii: S1097-2765(24)00831-1. [Epub ahead of print]
    mTORC1 activity licenses its own release from the lysosomal surface.
    Aishwarya Acharya, Constantinos Demetriades.
      Nutrient signaling converges on mTORC1, which, in turn, orchestrates a physiological cellular response. A key determinant of mTORC1 activity is its shuttling between the lysosomal surface and the cytoplasm, with nutrients promoting its recruitment to lysosomes by the Rag GTPases. Active mTORC1 regulates various cellular functions by phosphorylating distinct substrates at different subcellular locations. Importantly, how mTORC1 that is activated on lysosomes is released to meet its non-lysosomal targets and whether mTORC1 activity itself impacts its localization remain unclear. Here, we show that, in human cells, mTORC1 inhibition prevents its release from lysosomes, even under starvation conditions, which is accompanied by elevated and sustained phosphorylation of its lysosomal substrate TFEB. Mechanistically, "inactive" mTORC1 causes persistent Rag activation, underlining its release as another process actively mediated via the Rags. In sum, we describe a mechanism by which mTORC1 controls its own localization, likely to prevent futile cycling on and off lysosomes.
    Keywords:  GATOR1; Rag GTPases; Rheb; TFE3; TFEB; Torin1; lysosomes; mTORC1; rapamycin
    DOI:  https://doi.org/10.1016/j.molcel.2024.10.008
  2. Mol Cell. 2024 Oct 25. pii: S1097-2765(24)00832-3. [Epub ahead of print]
    mTORC1 restricts TFE3 activity by auto-regulating its presence on lysosomes.
    Susan Zwakenberg, Denise Westland, Robert M van Es, Holger Rehmann, Jasper Anink, Jolita Ciapaite, Marjolein Bosma, Ellen Stelloo, Nalan Liv, Paula Sobrevals Alcaraz, Nanda M Verhoeven-Duif, Judith J M Jans, Harmjan R Vos, Eleonora Aronica, Fried J T Zwartkruis.
      To stimulate cell growth, the protein kinase complex mTORC1 requires intracellular amino acids for activation. Amino-acid sufficiency is relayed to mTORC1 by Rag GTPases on lysosomes, where growth factor signaling enhances mTORC1 activity via the GTPase Rheb. In the absence of amino acids, GATOR1 inactivates the Rags, resulting in lysosomal detachment and inactivation of mTORC1. We demonstrate that in human cells, the release of mTORC1 from lysosomes depends on its kinase activity. In accordance with a negative feedback mechanism, activated mTOR mutants display low lysosome occupancy, causing hypo-phosphorylation and nuclear localization of the lysosomal substrate TFE3. Surprisingly, mTORC1 activated by Rheb does not increase the cytoplasmic/lysosomal ratio of mTORC1, indicating the existence of mTORC1 pools with distinct substrate specificity. Dysregulation of either pool results in aberrant TFE3 activity and may explain nuclear accumulation of TFE3 in epileptogenic malformations in focal cortical dysplasia type II (FCD II) and tuberous sclerosis (TSC).
    Keywords:  FCD IIb; NPRL2; Rag GTPases; Rheb; TFE3; TSC; amino acids; lysosomes; mTORC1
    DOI:  https://doi.org/10.1016/j.molcel.2024.10.009
  3. Trends Mol Med. 2024 Nov 01. pii: S1471-4914(24)00276-4. [Epub ahead of print]
    The dual role of the TSC complex in cancer.
    Josephine Hartung, Christine Müller, Cornelis F Calkhoven.
      The tuberous sclerosis complex (TSC1/TSC2/TBC1D7) primarily functions to inhibit the mechanistic target of rapamycin complex 1 (mTORC1), a crucial regulator of cell growth. Mutations in TSC1 or TSC2 cause tuberous sclerosis complex (TSC), a rare autosomal dominant genetic disorder marked by benign tumors in multiple organs that rarely progress to malignancy. Traditionally, TSC proteins are considered tumor suppressive due to their inhibition of mTORC1 and other mechanisms. However, more recent studies have shown that TSC proteins can also promote tumorigenesis in certain cancer types. In this review, we explore the composition and function of the TSC protein complex, the roles of its individual components in cancer biology, and potential future therapeutic targeting strategies.
    Keywords:  MYC; TSC; cancer; mTORC1; molecular glue degraders
    DOI:  https://doi.org/10.1016/j.molmed.2024.10.009
  4. FASEB J. 2024 Nov 15. 38(21): e70147
    HSP70 promotes amino acid-dependent mTORC1 signaling by mediating CHIP-induced NPRL2 ubiquitination and degradation.
    Jianfang Gao, Mingjun Lin, Jina Qing, Hongxia Li, Xiao Zeng, Wuzhou Yuan, Tingting Li, Shanping He.
      Mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth and its dysregulation leads to a variety of human diseases. Although NPRL2, an essential component of the GATOR1 complex, is reported to effectively suppress amino acid-induced mTORC1 activation, the regulation of NPRL2 protein stability is unclear. In this study, we show that chaperon-associated ubiquitin ligase CHIP interacts with NPRL2 and promotes its polyubiquitination and proteasomal degradation. Moreover, HSP70 mediates CHIP-induced ubiquitination and degradation of NPRL2. Consistently, overexpression of HSP70 enhances whereas HSP70 depletion inhibits amino acid-induced mTORC1 activation. Accordingly, knockdown of HSP70 promotes basal autophagic flux, and inhibits cell growth and proliferation. Taken together, these results demonstrated that HSP70 is a novel activator of mTORC1 through mediating CHIP-induced ubiquitination and degradation of NPRL2.
    Keywords:  CHIP; HSP70; NPRL2; amino acid; mTORC1; ubiquitination
    DOI:  https://doi.org/10.1096/fj.202401352R
  5. J Cell Biol. 2025 Jan 06. pii: e202403104. [Epub ahead of print]224(1):
    Activation of lysosomal Ca2+ channels mitigates mitochondrial damage and oxidative stress.
    Xinghua Feng, Weijie Cai, Qian Li, Liding Zhao, Yaping Meng, Haoxing Xu.
      Elevated levels of plasma-free fatty acids and oxidative stress have been identified as putative primary pathogenic factors in endothelial dysfunction etiology, though their roles are unclear. In human endothelial cells, we found that saturated fatty acids (SFAs)-including the plasma-predominant palmitic acid (PA)-cause mitochondrial fragmentation and elevation of intracellular reactive oxygen species (ROS) levels. TRPML1 is a lysosomal ROS-sensitive Ca2+ channel that regulates lysosomal trafficking and biogenesis. Small-molecule agonists of TRPML1 prevented PA-induced mitochondrial damage and ROS elevation through activation of transcriptional factor EB (TFEB), which boosts lysosome biogenesis and mitophagy. Whereas genetically silencing TRPML1 abolished the protective effects of TRPML1 agonism, TRPML1 overexpression conferred a full resistance to PA-induced oxidative damage. Pharmacologically activating the TRPML1-TFEB pathway was sufficient to restore mitochondrial and redox homeostasis in SFA-damaged endothelial cells. The present results suggest that lysosome activation represents a viable strategy for alleviating oxidative damage, a common pathogenic mechanism of metabolic and age-related diseases.
    DOI:  https://doi.org/10.1083/jcb.202403104
  6. Expert Opin Ther Targets. 2024 Nov 03. 1-11
    Targeted therapeutic strategies for the kidney.
    Fei Yuan, Lilach O Lerman.
       INTRODUCTION: Kidney diseases impose a significant burden with high incidence and mortality rates. Current treatment options for kidney diseases are limited, necessitating urgent development of novel and effective therapeutic strategies to delay or reverse disease progression. Targeted therapies for the kidney hold promise in significantly enhancing treatment outcomes, offering hope to patients afflicted with renal disorders.
    AREAS COVERED: This review summarized advances in kidney-targeted therapies including genes, peptides and proteins, cell-based, nanoparticles, and localized delivery routes. We also explored the potential clinical applications, prospects, and challenges of targeted therapies for renal disorders.
    EXPERT OPINION: Advances in targeted therapies for renal conditions have enhanced therapeutic outcomes. Clinical application of kidney-targeted therapies is currently limited by renal structure and the scarcity of robust biomarkers. Bridging the gap from basic and pre-clinical research targeting the kidney to achieving clinical translation remains a formidable challenge.
    Keywords:  Kidney-targeted therapies; cell-based therapy; gene-targeted therapy; localized delivery routes; nanoparticles; peptides and proteins targeted therapy
    DOI:  https://doi.org/10.1080/14728222.2024.2421756
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